Inherited metabolic disorders, in which the body is unable to break down a specific nutrient, are usually caused by an error in one gene and can cause a wide range of devastating health problems. Now an international team of researchers has found that a rare kind of genetic mutation, a repeat expansion, is to blame for three kinds of rare, undiagnosed conditions that affect children. These mutations are very challenging to identify; the whole genome has to be sequenced to reveal them because instead of a deleterious change in the sequence, the sequence is normal and nearby DNA is a few hundred times as long as it should be.

"To detect this kind of DNA multiplication, you can only use whole-genome sequencing and have to search through billions of pieces of DNA; it's truly a search for the needle in the haystack," explained the lead author of the study Dr. Clara van Karnebeek. "With our new approach we have finally solved our mystery cases, and we now expect to find the genetic cause of other, as of yet unexplained, genetic metabolic diseases."

Repetitive expansions of DNA are connected to around thirty different diseases.

"For kids with rare diseases and their families, finding the root causes of their disorders is tremendously important," said Dr. Wyeth Wasserman, a co-author of the study. "A diagnosis gives us the potential to intervene, relieves undeserved parental guilt, and provides insights into more common diseases."

Once the disease is diagnosed, researchers can pursue potential treatment avenues. They may aim to repair the genetic dysfunction or supplement the impaired nutrient or missing enzyme. Any intervention that can slow the progression of damage can improve the quality of life for patients and their families.

The researchers had to take a new approach to reveal the causative problem. Genes contain sequences that code for protein, called exons. Many times, scientists will only check those areas that code for protein to look for errors that lead to disease.

"In our search, we focused on variations that would have been hard to discover through exome sequencing," said Drögemöller. "After months of experimenting with various different analyses, we finally uncovered this novel genetic variant by using new targeted approaches aimed at identifying DNA repeat expansions."

"These findings were made possible by a multidisciplinary approach and advances in technology, techniques, and software," said Richmond. "It wouldn't have been possible as recently as two years ago and, most importantly, it shows us what to look for in other undiagnosed cases."

This work showed that an enzyme that normally converts an amino acid called glutamine to a molecule called glutamate - glutaminase, is involved in this disease. The scientists still have to figure out whether the symptoms are arising because glutamine is accumulating, or glutamate is absent. Affected children experience serious delays in developmental and problems with speech, language, balance, and coordination. It is a rare problem, having been found in one of 8,000 people. However, taken together, rare diseases with an unknown cause have a significant impact on the lives of many people.

"We can do better for children with rare diseases. For the 50 percent who can't find answers, this discovery and new approach will help us dig in and potentially find the causes of their disease," said Richmond.

The video above from the National Institutes of Health discusses tandem repeats in the mammalian genome.

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